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Overview

FOXO3, also known as FOXO3a (and previously as FKHRL1), is a Forkhead protein of the O subclass. FOXOs have overlapping expression profiles and activities, but FOXO3a is known to be particularly important in cell cycle control and apoptosis, the immune system, fertility, and longevity [1][2][3]. It has a widespread distribution in the body, although expression levels are not equal throughout tissues.

It contains a characteristic Forkhead box DNA binding domain, and is able to up- and downregulate expression of a variety of genes via binding of its consensus Forkhead Recognition Element, or similar sequences (including Insulin Response Elements). DNA recognition is performed by helix 3 of the DBD, although other parts of the DBD also contact the DNA to increase binding stability.

FOXO3 is a human orthologue of C. elegans's daf-16, a gene required for the long-lived phenotype of daf-2-null nematodes. FOXO3's involvement in longevity, aging and senescence may be linked to its roles in oxidative stress, as reactive oxygen species (ROS) are known to induce cellular senescence. FOXO3a is activated and upregulated in response to oxidative stress, where it upregulates the expression of antioxidants such as catalase, MnSOD or sestrin 3. In response to DNA damage, FOXO3 contributes to cell cycle arrest [4] and if necessary, helps bring about apoptosis by regulating genes such as Bim, PUMA and FLIP [5]. FOXO proteins are considered tumour suppressors; FOXO3a is very broadly anti-proliferative, and pro-apoptotic [6].

FOXO3a contains both nuclear export and nuclear import signals, allowing it to be localised in different subcellular areas, such as sequestration in the cytoplasm. It is regulated via a complex set of post-translational modifications including phosphorylation, methylation, acetylation and polyubiquitination. These covalent modifications affect stability, subcellular localisation, gene target specificity, and DNA binding activity [7]. One of the most famous and important FOXO3 regulators is the serine/threonine kinase Akt (PKB), downstream of PI-3-kinase, which inhibits FOXO3 activity by phosphorylating it at three sites throughout the protein. Regulation by acetylation includes SIRT (sirtuin) activity, which removes acetyl groups added by proteins including p300 and CBP, linking FOXO3 back to longevity. SIRT1 activity on FOXO3a apparently causes upregulation of survival genes such as GADD45, and reduces expression of apoptotic genes such as Bim, although it is not yet clear how this differential regulation is achieved [8].

As well as post-translational modifications, FOXO3 transcriptional activity is thought to be modulated by physical interactions with proteins such as β-catenin and RUNX3. Further, FOXO3a also affects the activity of other well-known TFs, performing inhibitory protein-protein interactions with p53 and ER, as well as potentially increasing ATM activity by binding to it.

Foxo3a-/- mice are viable (demonstrating partial redundancy between FoxOs) but show immune problems, such as autoinflammation and lymphoproliferation resulting from T helper cell hyperactivation, which itself is caused by overactivity of NFκB [9]. FOXO3 may be involved in the cardiovascular system, where its targets include eNOS and MuRF. Female Foxo3a-/- mice also have age-dependent infertility resulting from excessive follicular activation, suggesting that FOXO3a may regulate ovarian follicular development in humans [10].

References
  1. Maiese K et al. A "FOXO" in sight: targeting Foxo proteins from conception to cancer. Med Res Rev, 29(3):395-418. (PMID 18985696)
  2. Huang H and Tindall DJ. Dynamic FoxO transcription factors. J. Cell. Sci., 120(Pt 15):2479-87. (PMID 17646672)
  3. Maiese K et al. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. , 14(5):219-27. (PMID 18403263)
  4. Ho KK et al. Many forks in the path: cycling with FoxO. Oncogene, 27(16):2300-11. (PMID 18391972)
  5. Cornforth AN et al. FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells. Oncogene, 27(32):4422-33. (PMID 18391984)
  1. Dansen TB and Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol., 18(9):421-9. (PMID 18715783)
  2. Calnan DR and Brunet A. The FoxO code. Oncogene, 27(16):2276-88. (PMID 18391970)
  3. Vogt PK et al. Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle, 4(7):908-13. (PMID 15917664)
  4. Peng SL. Foxo in the immune system. Oncogene, 27(16):2337-44. (PMID 18391975)
  5. Brenkman AB and Burgering BM. FoxO3a eggs on fertility and aging. , 9(11):464-7. (PMID 14604822)
Figures
FIGURE 1 Phosphorylation of FOXO3a
Schematic figure showing confirmed sites of phosphorylation in FOXO3a, and the kinases involved. Phosphorylation by MST increases FOXO3 activity, while Akt, SGK, IKKβ and Erk are inhibitors. DBD = forkhead DNA binding domain, NLS = nuclear localisation sequence, NES = nuclear export signal, TAD = transactivation domain.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.